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PDBsum entry 4jm0
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Cell adhesion
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PDB id
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4jm0
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References listed in PDB file
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Key reference
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Title
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The structure of cytomegalovirus immune modulator ul141 highlights structural ig-Fold versatility for receptor binding.
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Authors
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I.Nemčovičová,
D.M.Zajonc.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2014,
70,
851-862.
[DOI no: ]
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PubMed id
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Abstract
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Natural killer (NK) cells are critical components of the innate immune system as
they rapidly detect and destroy infected cells. To avoid immune recognition and
to allow long-term persistence in the host, Human cytomegalovirus (HCMV) has
evolved a number of genes to evade or inhibit immune effector pathways. In
particular, UL141 can inhibit cell-surface expression of both the NK
cell-activating ligand CD155 as well as the TRAIL death receptors (TRAIL-R1 and
TRAIL-R2). The crystal structure of unliganded HCMV UL141 refined to 3.25 Å
resolution allowed analysis of its head-to-tail dimerization interface. A
`dimerization-deficient' mutant of UL141 (ddUL141) was further designed, which
retained the ability to bind to TRAIL-R2 or CD155 while losing the ability to
cross-link two receptor monomers. Structural comparison of unliganded UL141 with
UL141 bound to TRAIL-R2 further identified a mobile loop that makes intimate
contacts with TRAIL-R2 upon receptor engagement. Superposition of the Ig-like
domain of UL141 on the CD155 ligand T-cell immunoreceptor with Ig and ITIM
domains (TIGIT) revealed that UL141 can potentially engage CD155 similar to
TIGIT by using the C'C'' and GF loops. Further mutations in the TIGIT binding
site of CD155 (Q63R and F128R) abrogated UL141 binding, suggesting that the
Ig-like domain of UL141 is a viral mimic of TIGIT, as it targets the same
binding site on CD155 using similar `lock-and-key' interactions. Sequence
alignment of the UL141 gene and its orthologues also showed conservation in this
highly hydrophobic (L/A)X6G `lock' motif for CD155 binding as well as
conservation of the TRAIL-R2 binding patches, suggesting that these
host-receptor interactions are evolutionary conserved.
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